Coccidioidomycosis is a serious respiratory disease in the Sonoran Desert of southern Arizona and the central valley of California. There is currently no effective vaccine; some people can require life-long treatment with expensive antifungals. The goal of this R21 application is to understand the mechanism of protective immunity elicited by a novel attenuated mutant of Coccidioides, ?cps1. Preliminary data demonstrates both safety (no disease in profoundly immunocompromised mice) and profound protection from subsequent infection with wild-type Coccidioides in otherwise susceptible mice. Information is incomplete concerning the immune response(s) induced vaccination and which are responsible for protection are unknown. Here we will use the approaches of modern cellular immunology to determine the cellular mechanism of vaccination and which of the induced responses to ?cps1 are responsible for protection.